Previous investigations from our laboratory revealed that Notch is expressed by osteoblasts and its synthesis is regulated by glucocorticoids. Notch plays a critical role in osteoblastogenesis and its deletion results in serious developmental defects and neonatal lethality. Its over expression in the skeleton causes osteopenia secondary to an inhibitory effect on osteoblastogenesis. Although the activation of the canonical Notch signaling pathway induces the expression of hairy enhancer of split (HES)-1, HES-1 over expression does not recapitulate all the effects of Notch, and alternate signals, such as HEY-1 also play a role in the inhibitory effects of Notch in cells of the osteoblastic lineage. Central to the inhibitory actions of Notch is the suppression of the Wnt/?-catenin signaling pathway.
The aim of the proposed studies is to understand the function of Notch and HES-1 in bone in vivo and in vitro and define mechanisms involved. For this purpose, we will use transgenic mouse lines over expressing Notch or HES-1 in the bone environment, and mice carrying conditional deletions of notch1 and 2 or hes-1.
Our specific aims are: 1) To explore the mechanism of action of Notch in cells of the osteoblastic lineage, particularly mechanisms involved in its inhibitory effects on Wnt/?- catenin;2) To determine the function of HES-1 in vivo by transgenic over expression of HES-1 under the control of the type I collagen promoter, and by targeted hes-1 conditional deletion. The skeletal phenotype of mice misexpressing HES-1 will be compared to that of wild type mice and determined by histomorphometry, contact radiography, densitometry and micro CT scanning;and 3) To determine the mechanism of action of HES-1 in vitro and signals responsible for its effects on osteoblastogenesis. The impact of Notch and HES-1 on bone remodeling and mechanisms involved will be determined. These investigations should clarify the role of Notch and HES-1 in bone cell function.

Public Health Relevance

This project will provide novel information on intracellular proteins that regulate the function of bone forming cells, and is relevant to our understanding of mechanisms involved in osteoporosis and developments of new therapies for this disease.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Skeletal Biology Structure and Regeneration Study Section (SBSR)
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Malozowski, Saul N
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St. Francis Hospital and Medical Center
United States
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Canalis, Ernesto; Zanotti, Stefano; Smerdel-Ramoya, Anna (2014) Connective tissue growth factor is a target of notch signaling in cells of the osteoblastic lineage. Bone 64:273-80
Canalis, Ernesto; Kranz, Lauren; Zanotti, Stefano (2014) Nemo-like kinase regulates postnatal skeletal homeostasis. J Cell Physiol 229:1736-43
Zanotti, Stefano; Kalajzic, Ivo; Aguila, Hector Leonardo et al. (2014) Sex and genetic factors determine osteoblastic differentiation potential of murine bone marrow stromal cells. PLoS One 9:e86757
Zanotti, Stefano; Canalis, Ernesto (2013) Notch signaling in skeletal health and disease. Eur J Endocrinol 168:R95-103
Canalis, Ernesto (2013) Wnt signalling in osteoporosis: mechanisms and novel therapeutic approaches. Nat Rev Endocrinol 9:575-83
Zanotti, Stefano; Canalis, Ernesto (2013) Notch suppresses nuclear factor of activated T cells (NFAT) transactivation and Nfatc1 expression in chondrocytes. Endocrinology 154:762-72
Canalis, Ernesto; Adams, Douglas J; Boskey, Adele et al. (2013) Notch signaling in osteocytes differentially regulates cancellous and cortical bone remodeling. J Biol Chem 288:25614-25
Zanotti, Stefano; Smerdel-Ramoya, Anna; Canalis, Ernesto (2013) Nuclear factor of activated T-cells (NFAT)C2 inhibits Notch receptor signaling in osteoblasts. J Biol Chem 288:624-32
Zanotti, Stefano; Canalis, Ernesto (2013) Hairy and Enhancer of Split-related with YRPW motif (HEY)2 regulates bone remodeling in mice. J Biol Chem 288:21547-57
Canalis, Ernesto; Parker, Kristen; Feng, Jian Q et al. (2013) Osteoblast lineage-specific effects of notch activation in the skeleton. Endocrinology 154:623-34

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